The present invention relates to xcex2-phenylalanine derivatives, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis and ophthalmic diseases.
Integrins are heterodimeric transmembrane proteins located on the surface of cells, which play an important part in the adhesion of cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single-letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also referred to as the xcex1vxcex23 receptor, or alternatively the xcex1vxcex25 receptor or the GpIIb/IIIa receptor, play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Examples which may be mentioned are cancer, osteoporosis, arteriosclerosis, restenosis (fresh occurrence of a stenosis after a surgical intervention as a result of damage to the vascular wall) and ophthalmia (a certain type of inflammation of the eye).
The xcex1vxcex23 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the xcex1vP3 receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial requirement for tumor growth and metastasis formation in carcinomatous disorders. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the xcex1vxcex23 receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are caused by an inequilibrium between bone formation and bone degradation, i.e. the resorption of bone material caused by addition of osteoclasts predominates.
It was possible to show that the blocking of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their corresponding integrin receptors, for example by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Angiogenesis therefore does not occur, which leads to a stoppage or regression of tumour growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumour cells and thus their ability for metastasis formation are markedly decreased if their xcex1vxcex23 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can obviously be suppressed by blockage of the xcex1vxcex23 receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to resorb its substance (WO 98/18461, p.1, 1. 24 to p.2, 1. 13).
As a result of the blockage of the xcex1vxcex23 receptor on cells of the aorta smooth vascular musculature with the aid of integrin receptor antagonists, it is possible to suppress the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as antagonists of integrin receptors. For example, WO98/00395 discloses the para-substituted phenylalanine derivative (I), which exhibits an IC50 value of 0.13 nM in an xcex1vxcex23 receptor assay and an IC50 value of 0.16 nM in an xcex1vxcex25 receptor assay: 
xcfx89-Phenylcarboxylic acids having a phenyl residue which is linked to the phenyl group via a linker group and having a guanidine unit or a guanidine mimic are disclosed, for example in WO 97/36858, WO 97/36859, WO 97/36860 and WO 97/36862. According to these laid-open patent applications, the linker group can be an amide, sulphonamide, ester, urea, ether, thioether, sulphoxide, sulphone or ketone unit which may be extended by an additional methylene group, or can be a saturated or unsaturated alkylene bridge.
In particular, WO 97/36859, in addition to numerous substances comprised by a general formula, actually discloses 3-phenylpropionic acid derivatives such as (II) or (III). While the xcex1-phenylalanine derivative (II) exhibits an IC50 value of 0.18 nM with respect to its activity as an xcex1vxcex23 antagonist in in-vitro investigations, the succinic acid derivatives (III) have IC50 values in the range from 38.7 to 141 nLM in the same investigations: 
WO 97/36862, in addition to numerous substances comprised by a general formula, actually describes xcex2-substituted propionic acid derivatives such as (IV) or (V). The sulphonamide-bridged derivative (IV) exhibits an IC50 value of 16.7 nM with respect to its activity as an xcex1vxcex23 antagonist in in-vitro investigations, while the amide-bridged derivatives (V) have IC50 values in the range from 0.87 to 11.6 nM in the same investigations: 
None of the abovementioned laid-open patent applications, however, discloses xcex2-phenylalanine derivatives or their activity as xcex1vxcex23 antagonists.
xcex2-Phenylalanine derivatives as xcex1vxcex23 antagonists are disclosed, for example, in U.S. Pat. No. 5,639,765, WO 97/08145 and WO 97/36861, the linkage of the carboxyl residue to the central group consisting of two phenyl units bonded to one another via a linker group being carried out in these compounds, if a central group of this type is present at all, via the amino group. For example, the compound (VI) disclosed in WO 97/36861 exhibits an IC50 value of 1.66 nM with respect to its activity as an xcex1vxcex23 antagonist in in-vitro investigations. 
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the xcex1vxcex23 and/or the xcex1vxcex25 receptor.
The present object is achieved according to the invention by the xcex2-phenylalanine derivatives defined below. In particular, it has emerged that the xcex2-phenylalanine derivatives according to the invention have a very high activity as integrin antagonists, especially against the xcex1vxcex23 and/or the xcex1vxcex25 receptor.
The present invention relates to compounds of the general formula (1) 
wherein
R1 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, a hydroxyl residue or an alkoxy residue or is bonded to R3 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R2 is bonded and can optionally contain heteroatoms;
R3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, a hydroxyl residue or an alkoxy residue or is bonded to R2 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R3 is bonded and can optionally contain heteroatoms;
R4 is xe2x80x94SO2R4xe2x80x2, xe2x80x94COOR4xe2x80x3, xe2x80x94COR4xe2x80x2, xe2x80x94CONR4xe2x80x22 or xe2x80x94CSNR4xe2x80x22;
R4xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R4xe2x80x3 is a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R5 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue or a substituted or unsubstituted aryl residue;
R10 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted alkoxy residue or a halogen atom;
R11 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted alkoxy residue or a halogen atom;
L is xe2x80x94(CH2)mNHSO2(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2NH(CH2)nxe2x80x94, xe2x80x94(CH2)mNHCO(CH2)nxe2x80x94, xe2x80x94(CH2)mCONH(CH2)nxe2x80x94, xe2x80x94(CH2)mOCH2(CH2)nxe2x80x94, xe2x80x94(CH2)mCH2O(CH2)nxe2x80x94, xe2x80x94(CH2)mCOO(CH2)nxe2x80x94, xe2x80x94(CH2)mOOC(CH2)nxe2x80x94, xe2x80x94(CH2)mCH2CO(CH2)nxe2x80x94, xe2x80x94(CH2)mCOCH2(CH2)nxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94(CH2)mSCH2(CH2)nxe2x80x94, xe2x80x94(CH2)mCH2S(CH2)nxe2x80x94, xe2x80x94(CH2)mCH2SO(CH2)nxe2x80x94, xe2x80x94(CH2)mSOCH2(CH2)nxe2x80x94, xe2x80x94(CH2)mCH2SO2(CH2)nxe2x80x94 or xe2x80x94(CH2)mSO2CH2(CH2)nxe2x80x94, wherein m and n are each an integer of 0 or 1 and m+nxe2x89xa61;
R6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue or is bonded to one of R7, R8 or R9, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is N, O or S;
R7 is absent, is xe2x80x94H, a substituted or unsubstituted alkyl or cycloalkyl residue, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR7xe2x80x2, xe2x80x94COOR7xe2x80x2, or is bonded to one of R6, R8 or R9 with formation of an optionally substituted heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R7xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue which can be saturated or unsaturated and/or can contain further heteroatoms;
R8 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue or is bonded to one of R6, R7 or R9, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R8 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R9 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue or is bonded to one of R6, R7 or R8, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R9 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
and their physiologically acceptable salts and stereoisomers.
According to the invention, preferred compounds of the formula (1) are those in which
R1 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof;
R2 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue, an alkenyl residue, an alkinyl residue or a substituted derivative thereof; a hydroxyl residue or a C1-6-alkoxy residue or is bonded to R3 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R2 is bonded and can optionally contain heteroatoms;
R3 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue, an alkenyl residue, an alkinyl residue or a substituted derivative thereof; a hydroxyl residue or a C1-6-alkoxy residue or is bonded to R2 with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes the carbon atom to which R3 is bonded and can optionally contain heteroatoms;
R4 is xe2x80x94SO2R4xe2x80x2, xe2x80x94COOR4xe2x80x3, xe2x80x94COR4xe2x80x2, xe2x80x94CONR4xe2x80x22 or xe2x80x94CSNR4xe2x80x22;
R4xe2x80x2 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R4xe2x80x3 is a C1-6-alkyl residue, a C3-7-cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R5 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, a C1-6-alkoxy residue or a substituted derivative thereof;
R10 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, a C1-6-alkoxy residue or a substituted derivative thereof or F, Cl, Br or I;
R11 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof or F, Cl, Br or I;
L is xe2x80x94NHSO2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94, xe2x80x94NHSO2CH2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94CH2SO2NHxe2x80x94, xe2x80x94SO2NHCH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CH2NHCOxe2x80x94, xe2x80x94NHCOCH2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94CONHCH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2OCH2, xe2x80x94OCH2CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94 xe2x80x94CH2CH2Oxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CH2COOxe2x80x94, xe2x80x94COOCH2xe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94OOCCH2xe2x80x94, xe2x80x94CH2OOCxe2x80x94, xe2x80x94CH2COxe2x80x94, xe2x80x94COCH2xe2x80x94, xe2x80x94CH2CH2COxe2x80x94, xe2x80x94COCH2CH2xe2x80x94, xe2x80x94CH2COCH2xe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2SCH2, xe2x80x94SCH2CH2xe2x80x94, xe2x80x94CH2CH2Sxe2x80x94, xe2x80x94SOCH2xe2x80x94, xe2x80x94CH2SOxe2x80x94, xe2x80x94CH2SOCH2xe2x80x94, xe2x80x94SOCH2CH2xe2x80x94, xe2x80x94CH2CH2SOxe2x80x94, xe2x80x94SO2CH2xe2x80x94, xe2x80x94CH2SO2xe2x80x94, xe2x80x94CH2SO2CH2xe2x80x94, xe2x80x94CH2CH2SO2xe2x80x94 or xe2x80x94SO2CH2CH2xe2x80x94;
R6 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof or is bonded to one of R7, R8 or R9, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is O, N or S;
R7 is absent, is xe2x80x94H, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR7xe2x80x2, xe2x80x94COOR7xe2x80x2, or is bonded to one of R6, R8 or R9 with formation of an optionally substituted heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R7xe2x80x2 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof;
R8 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof or is bonded to one of R6, R7 or R9, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R8 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; and
R9 is hydrogen, a C1-6-alkyl residue, a C3-7-cycloalkyl residue, an aryl residue or a substituted derivative thereof or is bonded to one of R6, R7 or R8, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R9 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
Particularly preferred compounds of the formula (I) according to the present invention are those in which
R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, benzyloxy or is bonded to R3 with formation of an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring system which includes the carbon atom to which R2 is bonded and can optionally contain heteroatoms;
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, or is bonded to R2 with formation of an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring system which includes the carbon atom to which RW is bonded and can optionally contain heteroatoms;
R4 is xe2x80x94SO2R4 or xe2x80x94COR4xe2x80x2;
R4xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, lphenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonylpiperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl, 8-quinolinyl;
R5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl or 
R10 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyelobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, fluorine, chlorine, bromine or iodine;
R11 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, fluorine, chlorine, bromine or iodine;
L is xe2x80x94NHSO2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94, xe2x80x94NHSO2CH2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94CH2SO2NHxe2x80x94, xe2x80x94SO2NHCH2xe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CH2NHCOxe2x80x94, xe2x80x94NHCOCH2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94CONHCH2xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2OCH2, xe2x80x94OCH2CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94CH2CH2Oxe2x80x94;
R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a28) or is bonded to one of R7, R8 or R9, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is N, O or S;
R7 is absent, is xe2x80x94H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR7xe2x80x2, xe2x80x94COOR7xe2x80x2 or is bonded to one of R6, R8 or R9 with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R7xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a28) or is bonded to one of R6, R7 or R9, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R8 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; and
R9 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a28) or is bonded to one of R6, R7 or R8, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R9 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
According to a preferred embodiment, the present invention relates to compounds of the formula (1) in which
R4 is xe2x80x94SO2R4xe2x80x2;
R4xe2x80x2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;
L is xe2x80x94NHSO2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94, xe2x80x94NHSO2CH2xe2x80x94;
X is N;
and the other residues are as defined above.
According to a further preferred embodiment, the present invention relates to compounds of the formula (1) in which
R4 is xe2x80x94COR4;
R4xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)anilin, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methylbenzothiazol-2-yl, N-methoxycarbonylpiperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-phlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;
L is xe2x80x94NHSO2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94 or xe2x80x94NHSO2CH2xe2x80x94;
X is N;
and the other residues are as defined above.
According to yet a further preferred embodiment, the present invention relates to compounds of the formula (1) in which
R4 is xe2x80x94SO2R4xe2x80x2;
R4xe2x80x2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;
L is xe2x80x94NHCOxe2x80x94, xe2x80x94CH2NHCOxe2x80x94 or xe2x80x94NHCOCH2xe2x80x94;
X is N;
and the other residues are as defined above.
According to yet a further preferred embodiment, the present invention relates to compounds of the formula (1) in which
R4 is xe2x80x94SO2R4xe2x80x2;
R4xe2x80x2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonylpiperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, 2-chloropyridin-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;
L is xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2OCH2xe2x80x94, xe2x80x94CH2CH2Oxe2x80x94 or xe2x80x94OCH2CH2xe2x80x94;
X is N;
and the other residues are as defined above.
According to yet a further preferred embodiment, the present invention relates to compounds of the formula (1) in which
R4 is xe2x80x94SO2R4xe2x80x2;
R4xe2x80x2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, xe2x80x94C6(CH3)5, xe2x80x94CH2C6H2(CH3)3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2-acetamido-4-methyl-thiazol-5-yl, phenylethyl, 1-phenylpropyl, (S)-(+)-camphor-10-yl, (R)-(xe2x88x92)-camphor-10-yl, 2-phenylethenyl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphenyl, 2,5-dimethylphenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-methoxy)aniline, 4-acetamidophenyl, 2,2,2-trifluoroethyl, 5-chloro-3-methyl-benzothiazol-2-yl, N-methoxycarbonyl-piperidin-3-yl, thiophen-2-yl, isoxazol-5-yl, 2-chloropyridine-3-yl, pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyridine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)-camphan-1-yl, (R)-camphan-1-yl or 8-quinolinyl;
L is xe2x80x94NHSO2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94 or xe2x80x94NHSO2CH2xe2x80x94;
X is N;
R7 and R8 together form an ethylene group which bonds the nitrogen atom to which R7 is bonded to the nitrogen atom to which R9 is bonded;
and the other residues are as defined above.
The present invention furthermore relates to a process for the preparation of compounds of the formula (1) 
comprising the steps
a) reaction of a xcex2-amino acid of the formula (2) 
where
P is xe2x80x94(CH2)mNO2, xe2x80x94(CH2)mOxe2x80x94C1-6-alkyl, xe2x80x94(CH2)mSO2Pxe2x80x2, xe2x80x94(CH2)mCOPxe2x80x2, xe2x80x94(CH2)mCH2Oxe2x80x94C1-6-alkyl, where m in each case in an integer of 0 or 1;
Pxe2x80x2 is xe2x80x94OH, xe2x80x94Oxe2x80x94C1-6-alkyl, and the other residues are as defined above;
with a compound R4-A to give a compound of the formula (3), 
where
R4 is xe2x80x94SO2R4xe2x80x2, xe2x80x94COOR4xe2x80x3, or xe2x80x94COR4xe2x80x2;
R4xe2x80x2 and R4xe2x80x3 are as defined above;
A is xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94O-triflyl, xe2x80x94O-tosyl, xe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94COxe2x80x94C1-6-alkyl, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94C1-6-alkyl, xe2x80x94OC(CH3)xe2x95x90CH2;
and the other residues are as defined above;
b) conversion of the residue P into the residue Q, where
Q is xe2x80x94(CH2)mNH2, xe2x80x94(CH2)mOH, xe2x80x94(CH2)mCH2OH, xe2x80x94(CH2)mSO2A, xe2x80x94(CH2)mCOA,
A is as defined above;
m is an integer of 0 or 1;
c) reaction of the compound obtained from step b) with a compound of the formula (4) 
where
S is ASO2(CH2)nxe2x80x94, NH2(CH2)nxe2x80x94, ACO(CH2)nxe2x80x94, HOCH2(CH2)nxe2x80x94, M(CH2)nxe2x80x94, MCH2(CH2)nxe2x80x94, HSCH2(CH2)nxe2x80x94 or HS(CH2)nxe2x80x94, where n is an integer of 0 or 1;
M is a residue including Mg, Li, Cd or Sn;
A is as defined above; and
C is xe2x80x94NO2
xe2x80x83and
X, R7, R8, R9 and R11 are as defined above;
to give a compound of the formula (5) 
where the residues are as defined above;
d) if appropriate, conversion of C, if C is a nitro group, into an optionally cyclic urea, thiourea or guanidine unit with obtainment of the compound (1); and
e) if appropriate, removal of protective groups and/or derivatization of nitrogen atoms, which are present at preferred times within the preparation process, and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiologically acceptable salts by reaction with an inorganic or organic base or acid.
Preferably, in the process according to the invention the xcex2-amino acid of the formula (2) is obtained by reaction of malonic acid with a benzaldehyde derivative of the formula (2a) 
where R10 and P are as defined above, in the presence of ammonia, ammonium compounds or amines and, if appropriate, subsequent substitution in the xcex1-position to the terminal carboxyl group.
Furthermore, according to a preferred embodiment of the invention, the process comprises the conversion of the nitro group in step d) by reduction to the amino group, subsequent reaction with a carbonic acid ester derivative and, if appropriate, removal of protective groups present and/or reaction with a compound containing at least one amino group.
The present invention furthermore relates to a pharmaceutical composition which contains at least one of the compounds according to the invention described above.
The present invention furthermore relates to the use of the compounds according to the invention described above for the production of a pharmaceutical composition having integrin-antagonistic action.
The present invention furthermore relates to the use of the compounds according to the invention described above for the production of a pharmaceutical composition for the therapy and prophylaxis of cancer, osteolytic diseases such as osteoporosis, arteriosclerosis, restenosis and ophthalmic disorders.